This study tests the hypothesis that Metabolic Syndrome (MetSyn) decreases cerebral blood flow (CBF) more in females than males due in part to the sex-specific loss of COX vasodilation. Male and female participants will be enrolled in two groups: Health Controls versus participants with MetSyn.

The central hypothesis is that MetSyn decreases CBF more in females than males due in part to the sex-specific loss of COX vasodilation. This hypothesis is based on extensive preliminary data demonstrating MetSyn induces: 1) 3-fold larger reductions in CBF in females that abolish sex differences, 2) region-specific CBF reduction patterns, and 3) a greater loss of COX-mediated vasodilation in females.

This hypothesis is tested via three Specific Aims:

• Aim 1: Determine the extent of sex differences in MetSyn-driven CBF reductions. The investigators hypothesize females with MetSyn will demonstrate larger decrements in global, grey matter and white matter CBF versus males.
• Aim 2: Determine the sex-by-region interactions of MetSyn reductions in CBF. The investigators hypothesize females will demonstrate larger regional CBF declines-particularly in regions known to be impacted very early in brain pathologies and/or specifically impaired by insulin resistance.
• Aim 3: Determine the role of COX signaling in mediating CBF changes in MetSyn. The investigators hypothesize COX vasodilation is reduced more in females than males with MetSyn.

All consented participants will conduct a screening visit with a blood panel to identify control vs MetSyn eligibility.

Once eligible, participants complete three laboratory visits (each lasting about 2 hours):

1. Exercise Visit: VO2 Max, DEXA for adiposity quantification, NIH Toolbox to assess neurocognitive function
2. MRI Visit 1: blinded to either Placebo or Indomethacin
3. MRI Visit 2: blinded to either Placebo or Indomethacin

Inclusion Criteria (Healthy Controls):

• 18-45 years old
• Normal fasting values for blood glucose (less than 100 g/dl)
• Normal values for lipids (LDL cholesterol less than 130 mg/dl, triglycerides less than 150 mg/dl) and HDL (men greater than 40, women greater than 50 mg/dl)
• Women must have a predictable menstrual cycle. Females will be studied on cycle days 1-7 to minimize sex hormone differences and their potential confounding effects on vascular outcomes. Oral contraceptives are allowed, and women will be studied during their placebo phase.

Inclusion Criteria (Participants with Metabolic Syndrome):

• 18-45 years old

• Meet at least 3 of the 5 ATP MetSyn criteria. These are:

  1. Waist circumference greater than 102 cm (males) or 82 cm (females)
  2. Triglycerides greater than 150 mg/dL
  3. HDL cholesterol less than 40 mg/dL (males) or 50 mg/dL (females)
  4. Blood pressure greater than or equal to 130/85 mmHg
  5. Fasting plasma glucose greater than 110 mg/dL

Exclusion Criteria (Healthy Controls):

• Body Mass Index (BMI) greater than or equal to 25 kg/m2
• Blood pressure over 130/80 mmHg
• Meeting any of the 5 MetSyn criteria listed above.

Exclusion Criteria (all participants):

• Current smoker, defined as more than 5 cigarettes over past 30 days

• Current diagnosis or history of:

  • peripheral vascular disease
  • hepatic disease
  • renal disease
  • lung disease
  • gastrointestinal disorders/bleeding
  • hematologic disease
  • stroke
  • myocardial infarction
  • coronary heart disease
  • congestive heart failure
  • heart surgery
  • sleep apnea
  • autoimmune diseases
  • HIV
  • traumatic brain injury, concussion, stroke, or seizures
  • Asthma
  • Polycystic ovarian syndrome
  • Type II diabetes
  • Currently pregnant or breastfeeding
  • Current musculoskeletal injury
  • Medication use known to influence cardiovascular function, other than contraceptive hormones. Broadly, the classes of drugs relate to treating blood pressure, diabetes, cholesterol.
  • Claustrophobia

• Lactose intolerance

• Magnesium-restricted diet